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Phage Therapy's Latest Makeover

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Phage Therapy's Latest Makeover DispatchDate: 17.04.2019 · ProofNo: 133, p.1 news feature 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Credit: Dr. Robert Pope, National Biodefense Analysis & Countermeasures Center 30 31 32 33 Phage therapy’s latest makeover 34 35 As issues of product consistency, standardization and specificity are being tackled, can phage therapeutics—long 36 oversold and overhyped—finally realize their antibacterial potential? Charles Schmidt investigates. 37 38 Charles Schmidt 39 40 41 n May of 2018, an international team of million grant from the UCSD chancellor, Still, previous experience, mostly in 42 researchers and clinicians reported they the new Center for Innovative Phage the context of compassionate-use phage 43 successfully treated a seriously ill teenager Applications and Therapeutics (IPATH) treatments, has shown the approach to 44 I with cystic fibrosis who had disseminated is applying “the same principles of clinical be hit-and-miss, time-consuming and 45 infection by Mycobacterium abscessus with evaluation and development to phage expensive. To turn bacteriophage from 46 a cocktail of genetically engineered phage1. therapy that would be applied to any other a laboratory tool into an efficacious 47 According to the University of Pittsburgh’s therapeutic entity,” says center co-director therapeutic for broader markets, companies 48 Graham Hatfull, who led the research team, Robert Schooley, a physician and infectious are seeking to scale up production and 49 this accomplishment represents a number disease specialist at UCSD. deliver potent phage products under good 50 of firsts: the first genetically engineered A worsening crisis of multi-drug- manufacturing practices (GMP) quickly 51 phage treatment—in this case, to convert resistant (MDR) infections, along with and reliably. Can companies deliver on 52 a lysogenic phage to a lytic variety—and advanced technologies for characterizing expectations? We may get the answer soon 53 the first treatment of a mycobacterium. It viruses and their host interactions, is as several companies developing phage 54 also bodes well for a therapy that has long prompting a re-evaluation of phage therapy. therapies—AmpliPhi Biosciences, Adaptive 55 been dismissed by Western practitioners, as And pharma, which has steered clear of Phage Therapeutics and Intralytix— move 56 well as for the future of synthetic-biology antibiotics, let alone phage-derived ones, toward the clinic this year. 57 approaches to the vexing problem of may be taking notice. Johnson & Johnson . Q158Q2 antibiotic-resistant bacteria.m struck two deals centered on phage in 100 years of interlude 59 This news follows last year’s launch of a January: one with Locus Biosciences, worth First tested as a prophylactic against avian 60 phage translational research center at the upwards of $818 million, to develop CRISPR typhosis in rural France in 1919, cocktails 61 University of California, San Diego (UCSD), phages (Box 1), and the other with the Israeli of phages were used therapeutically in 62 another sign of optimism in this old but company BiomX, which is applying phage Europe and the United States during the 63 controversial approach for treating bacterial therapy to dysbiosis of the microbiome. pre-antibiotic era, and they are still prevalent 64 infections. Supported with a three-year, $1.2 in Russia and Central and Eastern Europe 65 A B C NATURE BIOTECHNOLOGY | www.nature.com/naturebiotechnology DispatchDate: 17.04.2019 · ProofNo: 133, p.2 news feature 66 67 68 But funding remained scarce and validated 69 Box 1 | Turning bacterial defenses on themselves evidence of reproducible clinical efficacy 70 remained elusive, so many companies went 71 There is yet another way researchers are virulence or resistance genes. Cofounders out of business. Today, of that cadre of 72 turning phage into therapy: by loading Timothy Lu and Xavier Duportet (now companies, only GangaGen in Bangalore, 73 them up with CRISPR–Cas systems that Eligo’s CEO) showed that they could India; Baltimore-based Intralytix; and Phage 74 target host genes—that is, using the very knock out a virulent strain of S. aureus Biotech of Rehovot, Israel, are in business. 75 system that bacteria evolved to eliminate while leaving an avirulent strain intact. Intralytix and Phage Biotech survived by 76 external threats, like a phage, against itself. Likewise, they could knock out antibiotic deploying phage in agriculture to control 77 Locus Biosciences is using Cas3, resistance genes from plasmids, preventing plant diseases, detect pathogens and assess 78 which differs from the more widely used the spread of resistance10,11. They are food safety (Table 1). 79 Cas9 in that it degrades its target via positioning themselves in the microbiome 80 an exonucleolytic activity, essentially space, with their lead indication being A center of excellence 81 destroying its target gene, rather than a gut pathogenic bacteria causing a rare In 2010, Texas A&M University launched 82 introducing double-strand breaks, (undisclosed) disease. the Center of Phage Technology (CPT), 83 which prepare a template for repair or Finally, Cambridge, UK, start-up with Ry Young, professor of biochemistry, 84 replacement. Cofounder and researcher at Nemesis Biosciences is developing a biophysics and biology, at the helm. Like 85 North Carolina State University Rodolphe platform of so-called ‘transmids’ that many of the companies, Young says CPT’s 86 Barrangou and colleagues published a borrows elements of phage biology to initial strategy was to focus on agriculture 87 foundational paper in 2013 in which they deliver RNA-guided nucleases to knock out and animal husbandry, “while avoiding 88 show that Cas systems targeting specific antimicrobial resistance genes. Transmids human involvement because of high 89 bacterial sequences can distinguish among carry only a short signal phage sequence regulatory loads.” Now that’s changing. 90 closely related species and can control the that is needed for packaging into a phage Like other facilities that work in this area, 91 number of individual strains in a mixture9. capsid. They are grown in a helper bacterial the CPT is overwhelmed with requests for 92 According to senior VP Joseph Nixon, host that harbors a defective phage particle. phages as treatment of last resort for patients 93 CRISPR–Cas3 efficiently kills target cells After being purified from the host bacteria, with MDR infections. Indeed, the recent 94 regardless of the function of the targeted the transmids invade the pathogenic resurgence in human interventions and 95 sequence, and multiplexing is possible, bacteria in what CSO Conrad Lichtenstein emergency investigational new drug (eIND) 96 which, like phage cocktails, forestalls the calls a “hit and run” attack: transmid DNA applications “has come out of nowhere as a 97 development of resistance. Their first trial, enters the host cell, replicates and expresses spontaneous reaction to the MDR problem,” 98 which is in the planning stages, could be the nuclease, inactivating resistance genes. Young says. 99 among the first controlled, randomized In this way, the strategy avoids waves of The CPT supplied phages for a highly 100 trials of bacteriophage therapy and the first phage infection against which the patient publicized eIND treatment in 2016. Tom 101 using engineered phage. might mount an immune response, and, Patterson, a UCSD professor of psychiatry, 102 Eligo Bioscience in Paris is developing since it avoids killing directly, the bacterial had picked up an MDR Acinetobacter 103 a non-replicative phage platform that pathogens are not under direct selection to baumannii infection during a trip to Egypt 104 carries Cas9 targeted to bacterial evolve resistance, Lichtenstein says. and was near death from organ failure 105 by the time his therapy was delivered. 106 Patterson’s wife, Steffanie Strathdee, an 107 epidemiologist at UCSD, helped coordinate 108 the phage treatments that ultimately saved 109 today, for wound infections, gastroenteritis, Then in the early 2000s the field her husband’s life3. Contributed by three 110 sepsis and other ailments. In the West, sputtered back into life. The rise of modern separate entities—the CPT; AmpliPhi 111 phage therapy was abandoned after broad- sequencing technology began to revive Biosciences; and the US Naval Medical 112 spectrum antibiotics came on the scene. interest in phage biology and suggested that Research Center (NMRC), which has been 113 Later, during the 1940s, the California molecular engineering and characterization researching phage since 2011 for possible 114 Institute of Technology’s Seymour Benzer could start to address such issues as battlefield use—the phages were given 115 pioneered work with bacteriophage T4 as product consistency (phage cocktails often daily for two months through a catheter 116 an experimental genetic tool, leading to contain more than ten phage strains), poor into Patterson’s abdomen, as well as 117 the deciphering of the central dogma of tissue distribution, pharmacodynamics through an intravenous line. Within days 118 molecular biology and spurring its rise as a and immunogenicity issues. Despite the of beginning treatment, Patterson awoke 119 field. However, for a variety of reasons—the difficulty of gaining intellectual property from a coma, and after three months he 120 preponderance of phage work on laboratory protection (the technology has been around was cleared of infection. He remains in 121 rather than pathogenic bacteria (which for nearly a century), the skepticism of good health. Meanwhile, Strathdee, who 122 often are already naturally resistant to traditional pharma and venture investors, is the associate dean of global health 123 bacteriophages) and a lack of peer-reviewed and the uncertainties surrounding clinical science at UCSD, and Schooley, who was 124 published data showing efficacy in animal trials and regulatory oversight, a clutch of Patterson’s treating physician, joined forces 125 models, not to mention political bias companies sprang up around the concept by to launch IPATH.
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